Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation

Chu, Erskine; Mychasiuk, Richelle; Hibbs, Margaret L.; Semple, Bridgette D.

doi:10.1186/s12974-021-02325-6

Cited by 72 publications

(47 citation statements)

References 187 publications

(151 reference statements)

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“…The over-opening of mPTP produces excessive ROS, leading to the damage of neuron, microglia and blood vessels [ 42 , 43 ]. Therefore, inhibition of over-opening of mPTP will alleviate cerebral ischemia/reperfusion injury [ 44 ]. In vitro experimental results indicated that as compared with free CsA, CsA@HFn significantly reduced the over-opening of mPTP, mitochondrial damage and ROS content in OGD/R injured SH-SY5Y cells.…”

Section: Discussionmentioning

confidence: 99%

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Cyclosporine A loaded brain targeting nanoparticle to treat cerebral ischemia/reperfusion injury in mice

Liu

Cheng

et al. 2022

J Nanobiotechnol

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Background Ischemic stroke is one of the main causes of death and disability in the world. The treatment for ischemic stroke is to restore blood perfusion as soon as possible. However, when ischemic brain tissue is re-perfused by blood, the mitochondrial permeability transition pore (mPTP) in neuron and microglia is excessively opened, resulting in the apoptosis of neuron and nerve inflammation. This aggravates nerve injury. Cyclosporine A (CsA) inhibits the over-opening of mPTP, subsequently reducing the release of ROS and the apoptosis of cerebral ischemia/reperfusion injured neuron and microglia. However, CsA is insoluble in water and present in high concentrations in lymphatic tissue. Herein, cerebral infarction tissue targeted nanoparticle (CsA@HFn) was developed to treat cerebral ischemia/reperfusion injury. Results CsA@HFn efficiently penetrated the blood-brain barrier (BBB) and selectively accumulated in ischemic area, inhibiting the opening of mPTP and ROS production in neuron. This subsequently reduced the apoptosis of neuron and the damage of BBB. Consequently, CsA@HFn significantly reduced the infarct area. Moreover, CsA@HFn inhibited the recruitment of astrocytes and microglia in ischemic region and polarized microglia into M2 type microglia, which subsequently alleviated the nerve inflammation. Conclusions CsA@HFn showed a significant therapeutic effect on cerebral ischemia/reperfusion injury by alleviating the apoptosis of neuron, nerve inflammation and the damage of BBB in ischemic area. CsA@HFn has great potential in the treatment of ischemic stroke. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

“…Microglia is immune effector cells inherent in the central nervous system, and it distributed in gray matter and white matter [ 44 ]. Microglia makes up about 10% of the total number of brain cells.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine A loaded brain targeting nanoparticle to treat cerebral ischemia/reperfusion injury in mice

Liu

Cheng

et al. 2022

J Nanobiotechnol

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“…Meanwhile, plenty of new drugs, such as luteolin ( Luo et al, 2019 ), ginsenoside Rg1 ( Chen et al, 2019a ), and baicalein ( Yang et al, 2019 ) were also found to play a neuroprotective role by targeting the PI3K-Akt signaling pathway after ischemic stroke. Erskine Chu et al summarized that dysregulated PI3K-AKT signaling in microglia could shape chronic neuroinflammation, and put forward the view that pharmacological manipulation of the PI3K-AKT signaling axis can yield neuroprotective effects based on various studies ( Chu et al, 2021 ). In addition, other top immune genes are IL6 and TNF, which are also important immunoinflammatory molecules that participated in ischemic stroke ( Chen et al, 2019b ; Jenny et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Construction Immune Related Feed-Forward Loop Network Reveals Angiotensin II Receptor Blocker as Potential Neuroprotective Drug for Ischemic Stroke

Cao

et al. 2022

Front. Genet.

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Ischemic stroke (IS) accounts for the leading cause of disability and mortality in China. Increasing researchers are studying the effects of neuroprotective agents on IS. However, the molecular mechanisms of feed-forward loops (FFLs) associated with neuroprotection in the pathogenesis of IS need to be further studied. A protein-protein interaction (PPI) network of IS immune genes was constructed to decipher the characters and excavate 3 hub genes (PI3K, IL6, and TNF) of immunity. Then, we identified two hub clusters of IS immune genes, and the cytokine-cytokine receptor interaction pathway was discovered on the pathway enrichment results of both clusters. Combined with GO enrichment analysis, the cytokines participate in the inflammatory response in the extracellular space of IS patients. Next, a transcription factor (TF)–miRNA–immune gene network (TMIGN) was established by extracting four regulatory pairs (TF–miRNA, TF–gene, miRNA–gene, and miRNA–TF). Then, we detected 3-node regulatory motif types in the TMIGN network. According to the criteria we set for defining 3-node motifs, the motif with the highest Z-score (3-node composite FFL) was picked as the statistically evident motif, which was merged to construct an immune-associated composite FFL motif-specific sub-network (IA-CFMSN), which contained 21 3-node FFLs composed of 13 miRNAs, 4 TFs, 9 immune genes, and 1 TF& immune gene, among which TP53 and VEGFA were prominent TF and immune gene, respectively. In addition, the immune genes in IA-CFMSN were used for identifying associated pathways and drugs to further clarify the immune regulation mechanism and neuroprotection after IS. As a result, 5 immune genes targeted by 20 drugs were identified and the Angiotensin II Receptor Blockers (ARBs) target AGTR1 was found to be a neuroprotective drug for IS. In the present study, the construction of IA-CFMSN provides IS immune-associated FFLs for further experimental studies, providing new prospects for the discovery of new biomarkers and potential drugs for IS.

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“…The chronicization of neuroinflammation results in strong changes in the inflammatory profile of microglia, as a consequence of a continuous release of neurotoxic inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines, including IL-1 and tumor necrosis factor TNF-α, clinically resulting in an increased predisposition to the development of cognitive impairment and therefore also associated mood disorders, such as depression [ 43 ].…”

Section: Cytokines and Neuroinflammationmentioning

confidence: 99%

Neuro-Inflammaging and Psychopathological Distress

et al. 2022

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Inflammaging is a low degree of chronic and systemic tissue inflammation associated with aging, and is intimately linked to pro-inflammatory mediators. These substances are involved in the pathogenesis of chronic inflammatory diseases and related psychopathological symptoms. When inflammation and aging affect the brain, we use the term neuro-inflammaging. In this review, we focused on the neuro-inflammatory process typical of advanced ages and the related psychopathological symptoms, with particular attention to understanding the immune-pathogenetic mechanisms involved and the potential use of immunomodulatory drugs in the control of clinical psychological signs. Inflammation and CNS were demonstrated being intimately linked in the neuro-inflammatory loop. IL-1, IL-6, TNF-a, COX and PGE are only partially responsible. BBB permeability and the consequent oxidative stress resulting from tissue damage make the rest. Some authors elaborated the “theory of cytokine-induced depression”. Inflammation has a crucial role in the onset symptoms of psychopathological diseases as it is capable of altering the metabolism of biogenic monoamines involved in their pathogenesis. In recent years, NSAIDs as an adjunct therapy in the treatment of relevant psychopathological disorders associated with chronic inflammatory conditions demonstrated their efficacy. Additionally, novel molecules have been studied, such as adalimumab, infliximab, and etanercept showing antidepressant and anxiolytic promising results. However, we are only at the beginning of a new era characterized by the use of biological drugs for the treatment of inflammatory and autoimmune diseases, and this paper aims to stimulate future studies in such a direction.

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Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation

Cited by 72 publications

References 187 publications

Cyclosporine A loaded brain targeting nanoparticle to treat cerebral ischemia/reperfusion injury in mice

Cyclosporine A loaded brain targeting nanoparticle to treat cerebral ischemia/reperfusion injury in mice

Construction Immune Related Feed-Forward Loop Network Reveals Angiotensin II Receptor Blocker as Potential Neuroprotective Drug for Ischemic Stroke

Neuro-Inflammaging and Psychopathological Distress

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